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With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. 3909 of the 49 731 D:A:D study participants died during the 308 719 person-years of follow-up (crude incidence mortality rate, 12·7 per 1000 person-years [95% CI 12·3–13·1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17·5 in 1999–2000 to 9·1 in 2009–11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5·9 to 2·0), deaths from liver disease (2·7 to 0·9), and cardiovascular disease deaths (1·8 to 0·9). However, non-AIDS cancers increased slightly from 1·6 per 1000 person-years in 1999–2000 to 2·1 in 2009–11 (p=0·58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009–11 vs 1999–2000: 0·92 [0·70–1·22]). However, all-cause (0·72 [0·61–0·83]), liver disease (0·48 [0·32–0·74]), and cardiovascular disease (0·33 [0·20–0·53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999–2000 and 141/627 [22%] in 2009–11) and liver-related (40/256 [16%] in 1999–2000 and 64/627 [10%] in 2009–11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999–2000 to 142/627 [23%] in 2009–11). Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. Updated total numbers of deaths in children aged 0–27 days and 1–59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1–59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. Of 7·6 million deaths in children younger than 5 years in 2010, 64·0% (4·879 million) were attributable to infectious causes and 40·3% (3·072 million) occurred in neonates. Preterm birth complications (14·1%; 1·078 million, uncertainty range [UR] 0·916–1·325), intrapartum-related complications (9·4%; 0·717 million, 0·610–0·876), and sepsis or meningitis (5·2%; 0·393 million, 0·252–0·552) were the leading causes of neonatal death. In older children, pneumonia (14·1%; 1·071 million, 0·977–1·176), diarrhoea (9·9%; 0·751 million, 0·538–1·031), and malaria (7·4%; 0·564 million, 0·432–0·709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2·7% (0·205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0·451 million [0·339–0·547], 0·363 million [0·283–0·419], and 0·359 million [0·215–0·476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010–15 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. Continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates. The Bill & Melinda Gates Foundation.

There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under the framework of HIV treatment as prevention (TasP). However, population-level sustainability of this strategy has not been characterized. We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count, drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regression models over the study period, to relate estimated HIV incidence and the number of individuals on HAART and the percentage of virologically suppressed individuals. HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associated with increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per 100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, our models suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and for every 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%. Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained and profound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-term effectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with no financial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health Organization Antiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly within generalized epidemics, and resource-limited setting, as advocated by UNAIDS.

'AIDS' in chimpanzees There are more than 40 different types of simian immunodeficiency virus (SIV) infecting African primates, two of which crossed the species barrier to produce the AIDS viruses HIV-1 and HIV-2 in humans. Now a comprehensive natural history study of free-ranging chimpanzees in Gombe National Park has overturned a common assumption about SIVcpz, the precursor of HIV-1. It has been widely assumed that all SIVs are non-pathogenic in their natural hosts. But this new study, which followed 94 chimpanzees for over 9 years, shows that SIVcpz infection is associated with AIDS-like signs in chimpanzees, including a more than 10-fold increase in mortality risk, reduced fertility and progressive CD4 + T-cell depletion. By comparing the disease-causing mechanisms of these related retroviruses in humans and chimpanzees it may be possible to identify viral and host factors of interest to developers of drugs and vaccines for the prevention and treatment of HIV infection. There are over 40 different simian immunodeficiency viruses (SIVs) with which African primates are naturally infected; two of these have crossed the species barrier to generate human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Although SIVs do not generally cause AIDS in primates, AIDS-like disease is now shown to occur in chimpanzee populations in the wild who are naturally infected with SIVcpz, a close relative of HIV-1. African primates are naturally infected with over 40 different simian immunodeficiency viruses (SIVs), two of which have crossed the species barrier and generated human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) 1 , 2 . Unlike the human viruses, however, SIVs do not generally cause acquired immunodeficiency syndrome (AIDS) in their natural hosts 3 . Here we show that SIVcpz, the immediate precursor of HIV-1, is pathogenic in free-ranging chimpanzees. By following 94 members of two habituated chimpanzee communities in Gombe National Park, Tanzania, for over 9 years, we found a 10- to 16-fold higher age-corrected death hazard for SIVcpz-infected ( n = 17) compared to uninfected ( n = 77) chimpanzees. We also found that SIVcpz-infected females were less likely to give birth and had a higher infant mortality rate than uninfected females. Immunohistochemistry and in situ hybridization of post-mortem spleen and lymph node samples from three infected and two uninfected chimpanzees revealed significant CD4 + T-cell depletion in all infected individuals, with evidence of high viral replication and extensive follicular dendritic cell virus trapping in one of them. One female, who died within 3 years of acquiring SIVcpz, had histopathological findings consistent with end-stage AIDS. These results indicate that SIVcpz, like HIV-1, is associated with progressive CD4 + T-cell loss, lymphatic tissue destruction and premature death. These findings challenge the prevailing view that all natural SIV infections are non-pathogenic and suggest that SIVcpz has a substantial negative impact on the health, reproduction and lifespan of chimpanzees in the wild.

Health data disaggregated by sex is vital for identifying the distribution of illness, and assessing risk exposures, service access, and utilization. Disaggregating data along a health pathway, i.e., the measurable continuum from risk factor exposure to final health outcome (death), and including disease prevalence and a three-step care cascade (diagnosis, treatment, and control), has the potential to provide a holistic and systematic source of information on sex- and gender-based health inequities and identify opportunities for more tailored interventions to reduce those inequities. We collected sex- and age-disaggregated data along the health pathway. We searched for papers using global datasets on the sex-disaggregated care cascade for eight major conditions and identified cascade data for only three conditions: hypertension, diabetes, and HIV and AIDS. For each condition, we collected risk factor prevalence, disease prevalence, cascade progression, and death rates. We assessed the sex difference for all steps along the pathway and interpreted inequities through a lens of gender analysis. Sex-disaggregated data on risk factors, disease prevalence, and mortality were found for all three conditions across 204 countries. Sex-disaggregated care cascades for hypertension, diabetes, and HIV and AIDS were found only for 200, 39, and 76 countries, respectively. Significant sex differences were found in each step along the pathways. In many countries, males exhibited higher disease prevalence and death rates than females, while in some countries, they also reported lower rates of healthcare seeking, diagnosis, and treatment adherence. Smoking prevalence was higher among males in most countries, whereas prevalence of obesity and unsafe sex were higher in females in most countries. Findings support the increasing need to develop strategies that encourage greater male participation in preventive and healthcare service and underscore the importance of sex-disaggregated data in understanding health inequities and guiding gender-responsive interventions at different points along the pathway. Despite limitations in data availability and completeness, this study elucidates the need for more comprehensive and harmonized datasets for these and other conditions to monitor sex differences and implement sex-/gender-responsive interventions along the health pathway.

AIDS vaccine rethink Recent setbacks have prompted a major re-evaluation of the AIDS vaccine field. One question that has been asked is whether to continue development of T-cell-based HIV-1 vaccines. Now a study of a new vaccine in monkeys challenged with simian immunodeficiency virus (SIV) suggests that the T-cell-based strategy remains potentially viable. The vaccine was prepared using two adenovirus vectors (rAd26 prime/rAd5 boost) expressing SIV Gag protein. It induced potent T-cell immune responses and some protection from infection. These findings provide pointers to the design of a new generation of T-cell-based vaccine candidates for HIV-1. Vaccine elicted Gag specific cellular immune responses are shown to provide a measure of protection from disease in Mamu-A*01 -negative rhesus monkeys challenged with SIV MAC251 . A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans 1 , 2 . Consistent with these results, preclinical studies have demonstrated that rAd5 vectors expressing simian immunodeficiency virus (SIV) Gag failed to reduce peak or setpoint viral loads after SIV challenge of rhesus monkeys ( Macaca mulatta ) that lacked the protective MHC class I allele Mamu-A*01 (ref. 3 ). Here we show that an improved T-cell-based vaccine regimen using two serologically distinct adenovirus vectors afforded substantially improved protective efficacy in this challenge model. In particular, a heterologous rAd26 prime/rAd5 boost vaccine regimen expressing SIV Gag elicited cellular immune responses with augmented magnitude, breadth and polyfunctionality as compared with the homologous rAd5 regimen. After SIV MAC251 challenge, monkeys vaccinated with the rAd26/rAd5 regimen showed a 1.4 log reduction of peak and a 2.4 log reduction of setpoint viral loads as well as decreased AIDS-related mortality as compared with control animals. These data demonstrate that durable partial immune control of a pathogenic SIV challenge for more than 500 days can be achieved by a T-cell-based vaccine in Mamu-A*01 -negative rhesus monkeys in the absence of a homologous Env antigen. These findings have important implications for the development of next-generation T-cell-based vaccine candidates for HIV-1.

Antiretroviral therapy (ART) prevents human immunodeficiency virus (HIV) disease progression, mortality and transmission. We assess the impact of expanded HIV treatment for the prevention of Acquired Immunodeficiency Syndrome (AIDS)-related deaths and simulate four treatment scenarios for Nigeria and South Africa. For 1990-2013, we used the Joint United Nations Programme on HIV/AIDS (UNAIDS) database to examine trends in AIDS deaths, HIV incidence and prevalence, ART coverage, annual AIDS death rate, AIDS death-to-treatment and HIV infections to treatment ratios for the top 30 countries with the highest AIDS mortality burden and compare them with data from high-income countries. We projected the 1990-2020 AIDS deaths for Nigeria and South Africa using four treatment scenarios: 1) no ART; 2) maintaining current ART coverage; 3) 90% ART coverage based on 2013 World Health Organization (WHO) ART guidelines by 2020; and 4) reaching the United Nations 90-90-90 Target by 2020. In 2013, there were 1.3 million (1.1 million-1.6 million) AIDS deaths in the top 30 countries representing 87% of global AIDS deaths. Eight countries accounted for 58% of the global AIDS deaths; Nigeria and South Africa accounted for 27% of global AIDS deaths. The highest death rates per 1000 people living with HIV were in Central African Republic (91), South Sudan (82), Côte d'Ivoire (75), Cameroon (72) and Chad (71), nearly 8-10 times higher than the high-income countries. ART access in 2013 has averted as estimated 1,051,354 and 422,448 deaths in South Africa and Nigeria, respectively. Increasing ART coverage in these two countries to meet the proposed UN 90-90-90 Target by 2020 could avert 2.2 and 1.2 million deaths, respectively. Over the past decade the expansion of access to ART averted millions of deaths. Reaching the proposed UN 90-90-90 Target by 2020 will prevent additional morbidity, mortality and HIV transmission. Despite progress, high-burden countries will need to accelerate access to ART treatment to avert millions of premature AIDS deaths and new HIV infections.

Deaths from AIDS (1 500 000 in 2013) have been falling more slowly than anticipated with improved access to antiretroviral therapy. Opportunistic infections account for most AIDS-related mortality, with a median age of death in the mid-30s. About 360 000 (24%) of AIDS deaths are attributed to tuberculosis. Fungal infections deaths in AIDS were estimated at more than 700 000 deaths (47%) annually. Rapid diagnostic tools and antifungal agents are available for these diseases and would likely have a major impact in reducing deaths. Scenarios for reduction of avoidable deaths were constructed based on published outcomes of the real-life impact of diagnostics and generic antifungal drugs to 2020. Annual deaths could fall for cryptococcal disease by 70 000, Pneumocystis pneumonia by 162 500, disseminated histoplasmosis by 48 000 and chronic pulmonary aspergillosis by 33 500, with approximately 60% coverage of diagnostics and antifungal agents; a total of >1 000 000 lives saved over 5 years. If factored in with the 90–90–90 campaign rollout and its effect, AIDS deaths could fall to 426 000 annually by 2020, with further reductions possible with increased coverage. Action could and should be taken by donors, national and international public health agencies, NGOs and governments to achieve the UNAIDS mortality reduction target, by scaling up capability to detect and treat fungal disease in AIDS. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.

Previously, we reported that HIV-1 patients infected with CRF07_BC had significantly lower viral loads than those infected with subtype B. Since HIV-1 viral load is associated with AIDS disease progression, the current study was to link multiple clinical and molecular databases, and compare clinical outcomes of HIV-1patients infected with CRF07_BC, CRF01_AE and subtype B in Taiwan. Molecular genotyping data of 2,982 HIV-1/AIDS patients were submitted to Taiwan CDC HIV-1/AIDS case management database. Then the database was linked to Taiwan National Health Insurance Research database and National Cause of Death database from 2000−2016. Subsequently, a subtype-based HIV/AIDS clinical database containing 1,605 patients including 858 (53.5%) subtype B, 690 (43.0%) CRF07_BC and 57 (3.5%) CRF01_AE patients was successfully established and the clinical outcomes and survival of these patients were analyzed. Analysis of transmission route showed this HIV-1/AIDS cohort consists of 761 (47.4%) men who have sex with men (MSM), 132 (8.2%) heterosexuals and 712 (44.4%) injection drug user (IDUs). Survival analysis showed subtype B patients had a significantly lower death rate (8.2%) than CRF07_BC and CRF01-AE patients (22.8% and 22.8%, respectively). The higher death rate for CRF07_BC versus subtype B patients could be largely influenced by transmission route (IDU: 95.7% vs. 3.9%; MSM: 85.8% vs. 2.0%), as well as lower ART uptake rates (69.9% vs. 96.3%). Indeed, subset analysis among IDU patients, CRF07_BC-infected patients had a better 16-year survival rate than patients infected with subtype B (74.3% vs. 45.7%, p < 0.05). Our findings suggest that the transmission route is one major factor influencing death rate, while ART treatment and HIV-1 subtypes may also play important roles. Our study is the largest long-term cohort study of patients infected with CRF07_BC and subtype B in the same geographic region.

For the past few months, the Africa Centres for Disease Control and Prevention (Africa CDC) in Addis Ababa, where we work, has been developing this, with leaders from the African Union and in global health. [...]one of us (J.N.) was working in Côte d'Ivoire as part of a US Centers for Disease Control and Prevention project that was struggling to combat HIV in the country without access to medicine. The World Bank estimates that economic growth in sub-Saharan Africa will decline from 2.4% in 2019 to between -2.1 and -5.1% in 2020, the first recession in the region in 25 years. In August, the African Union Bureau of Heads of State and Government endorsed the strategy put forward by Africa CDC, reiterating how past experience in global health shows that Africa must move decisively, effectively and collectively to secure access to vaccines and life-saving therapy.